Periodontitis results in loss of tooth-supporting tissues including bone, cementum, and periodontal ligament (PDL), ultimately leading to tooth loss if left untreated. Dental tissue loss represents the second largest patient population next to blood transfusion. With current therapies, these tooth-supporting defects can be repaired to some degree, but the results are often disappointing. Growth factors stimulate bone and soft tissue repair when delivered to periodontal bone lesions. However, human trials have failed to show consistent results in promoting regeneration. During our initial grant period, we have demonstrated that the mode of delivery and the coordination of growth factors such as BMP7 (osteoinductive) and PDGF (angiogenic and mitogenic) are critical for tissue engineering of alveolar bone defects. The hallmark of periodontal disease is the chronic and inflammatory nature of the process. However, current technologies for periodontal tissue engineering have only focused on the use of singular regenerative factors or cells, without addressing the host response or influence of contaminating microbiota. Approaches that can not only control the regenerative processes of tissue neogenesis, but also address exuberant inflammatory responses and microbial infection may be valuable. In this competing renewal proposal, we hypothesize that the robust regeneration of chronic inflammatory periodontal lesions can be achieved by coordinating the regenerative activities with the anti- matrix metalloproteinase (MMP) and anti-microbial activities via a growth factor-enhanced bioactive scaffold. For our studies, the following specific aims are proposed: SA 1. Develop nanospheres incorporated into nano-fibrous scaffolds for controlled local delivery of MMP- inhibitory/antimicrobial agents. SA 2. Develop nano-fibrous scaffold with triple-loaded nanospheres to deliver PDGF, BMP7, and MMP- inhibitory/antimicrobial agents;and optimize the combination of their release profiles to maximize periodontal regeneration in vivo. SA 3. Confirm that the nanosphere/nano-fibrous scaffold, selected based on the results from aims 1 and 2, provides a superior environment for regeneration of periodontal tissues in chronic pathogen-induced periodontal wound models. PUBLIC HEALTH RELEVANCE: Periodontitis afflicts over 50% of the adult population in the United States without a predictable treatment outcome due to its chronic inflammatory nature, with approximately 10% displaying severe disease concomitant with early tooth loss. This project should significantly advance our capacity to design a modality for restoring periodontal wounds resulted from periodontitis, leading to advanced new regenerative therapies.